Anti-viral defence by an mRNA ADP-ribosyltransferase that blocks translation

Nature, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 23, 2024

Abstract Host–pathogen conflicts are crucibles of molecular innovation 1,2 . Selection for immunity to pathogens has driven the evolution sophisticated mechanisms throughout biology, including in bacterial defence against bacteriophages 3 Here we characterize widely distributed anti-phage system CmdTAC, which provides robust infection by T-even family phages 4 Our results support a model CmdC detects sensing viral capsid proteins, ultimately leading activation toxic ADP-ribosyltransferase effector protein, CmdT. We show that newly synthesized protein triggers dissociation chaperone from CmdTAC complex, destabilization and degradation antitoxin CmdA, with consequent liberation CmdT ADP-ribosyltransferase. Notably, does not target DNA or structured RNA, known targets other ADP-ribosyltransferases. Instead, modifies N6 position adenine GA dinucleotides within single-stranded RNAs, arrest mRNA translation inhibition replication. work reveals novel mechanism anti-viral previously unknown but broadly class ADP-ribosyltransferases mRNA.

Language: Английский

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Chromosomal integrons are genetically and functionally isolated units of genomes

Nucleic Acids Research, Journal Year: 2024, Volume and Issue: 52(20), P. 12565 - 12581

Published: Sept. 23, 2024

Abstract Integrons are genetic elements that increase the evolvability of bacteria by capturing new genes and stockpiling them in arrays. Sedentary chromosomal integrons (SCIs) can be massive highly stabilized structures encoding hundreds genes, whose function remains generally unknown. SCIs have co-evolved with host for aeons intertwined their physiology from a mechanistic point view. But, paradoxically, other aspects, like variable content location within genome, suggest high functional independence. In this work, we explored connection to genome using as model Superintegron (SI), 179-cassette long SCI Vibrio cholerae N16961. We relocated deleted SI SeqDelTA, novel method allows counteract strong stabilization conferred toxin–antitoxin systems array. characterized depth impact V. cholerae’s physiology, measuring fitness, chromosome replication dynamics, persistence, transcriptomics, phenomics, natural competence, virulence resistance against protist grazing. The deletion did not produce detectable effects any condition, proving that—despite millions years co-evolution—SCIs genetically functionally isolated units genomes.

Language: Английский

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Isolation, Characterization, and Unlocking the Potential of Mimir124 Phage for Personalized Treatment of Difficult, Multidrug-Resistant Uropathogenic E. coli Strain

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(23), P. 12755 - 12755

Published: Nov. 27, 2024

Escherichia coli and its bacteriophages are among the most studied model microorganisms. Bacteriophages for various E. strains can typically be easily isolated from environmental sources, many of these viruses harnessed to combat infections in humans animals. However, some relatively rare pose significant challenges finding suitable phages. The uropathogenic strain UPEC124, a patient suffering neurogenic bladder dysfunction, was found resistant all coliphages our collections, initial attempts isolate new phages failed. Using an improved procedure phage enrichment, we N4-related Mimir124, belonging Gamaleyavirus genus, which able lyse this “difficult” strain. Although Mimir124 is narrow-spectrum phage, it effective individualized treatment patient, leading pathogen eradication. primary receptor O antigen O101 type; consequently, Mimir124-resistant clones were rough (having lost antigen). These clones, however, gained sensitivity that recognize outer membrane proteins as receptors. Despite presence nine potential antiviral systems genome UPEC124 strain, difficulty largely due efficient, non-specific cell surface protection provided by antigen. results highlight importance approach therapy, where narrow host-range phages—typically avoided pre-fabricated cocktails—may instrumental. Furthermore, study illustrates how integrating genomic, structural, functional insights guide development innovative therapeutic strategies, paving way broader applications therapy combating multidrug-resistant bacterial pathogens.

Language: Английский

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Standardization of the Agar Plate Method for Bacteriophage Production

Antibiotics, Journal Year: 2024, Volume and Issue: 14(1), P. 2 - 2

Published: Dec. 24, 2024

The growing threat of antimicrobial resistance (AMR), exacerbated by the COVID-19 pandemic, highlights urgent need for alternative treatments such as bacteriophage (phage) therapy. Phage therapy offers a targeted approach to combat bacterial infections, particularly those resistant conventional antibiotics. This study aimed standardize an agar plate method high-mix, low-volume phage production, suitable personalized Plaque assays were conducted with double-layer method, and plaque sizes precisely measured using image analysis tools. Regression models developed Minitab software established correlations between size optimizing production while minimizing development. resulting Size Calculation (PSC) model accurately correlated inoculum concentration yield, establishing specific plaque-forming unit (PFU) thresholds optimal production. Using phages targeting pathogens Escherichia, Salmonella, Staphylococcus, Pseudomonas, Chryseobacterium, Vibrio, Erwinia, Aeromonas confirmed model's accuracy across various conditions. validation showed strong inverse correlation minimum-lawn cell clearing PFUs (MCPs; R² = 98.91%) identified density that maximizes yield evolution mutants. These results highlight PSC standardized scalable efficient which is crucial AMR management. Furthermore, its adaptability different conditions positions it potential standard tool rapid precise screening propagation in both clinical industrial settings.

Language: Английский

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